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钙调磷酸酶抑制剂(calcineur ininhibitors,CNIs)是一类通过抑制钙调磷酸酶而发挥免疫抑制作用的药物。临床上以他克莫司(FK-506)及环孢素A(CsA)为代表。该类药物大大提高移植效果同时也增加了移植术后糖尿病(post-transplantation diabetes mellitus,PTDM)的发病率,研究发现CNIs引起PTDM主要与钙调磷酸酶被抑制有关。CNIs抑制钙调磷酸酶,导致胞浆内T细胞活化核因子(cytosolic nuclear factor of activated Tcells,NFATc)去磷酸化受阻,抑制了NFATc1诱导的β细胞增殖,使β细胞数量进行性减少,胰岛素分泌减少,最终导致PTDM的发生。在高血糖的环境中,CNIs抑制钙调磷酸酶,可引起cAMP介导的反应结合蛋白活性调节转导子(transducer of regulated CRE Bactivity2,TORC2)持续磷酸化,抑制TORC2的入核及cAMP介导的反应结合蛋白(cAMP response element binding protein,CREB)的激活,引起靶基因的转录受抑,加重PTDM。此外,胰岛β细胞中含量很高的FK-506结合蛋白12(FK506-binding protein,FKBP-12)可导致FK506在β细胞聚集,而同等剂量的CsA无此分布规律,这可能是服用FK506的患者比服用CsA的患者PTDM的发病率更高的原因。
Calcineurin inhibitors (CNIs) are a class of drugs that exert immunosuppressive effects by inhibiting calcineurin. Clinically, tacrolimus (FK-506) and cyclosporin A (CsA) as the representative. These drugs greatly improve the transplanting effect and also increase the incidence of post-transplantation diabetes mellitus (PTDM). The study found that CNIs cause PTDM mainly associated with inhibition of calcineurin. CNIs inhibit calcineurin, leading to inhibition of cytosolic nuclear factor of activated T cells (NFATc) dephosphorylation, inhibition of NFATc1-induced β-cell proliferation, progressive decrease of β-cell number and secretion of insulin Reduce, eventually lead to the occurrence of PTDM. In hyperglycemic environment, CNIs inhibit calcineurin, which can cause continuous phosphorylation of cAMP-mediated transducer of regulated CREBB2 (TORC2), inhibit nuclear translocation of TORC2 and cAMP-mediated Activation of cAMP response element binding protein (CREB) causes repression of target gene transcription and aggravates PTDM. In addition, high levels of FK506-binding protein (FKBP-12) in islet β cells lead to FK506 accumulation in β-cells, while the same dose of CsA has no such distribution, which may be caused by FK506 Patients have a higher incidence of PTDM than patients taking CsA.